Hyaluronan Synthase Elevation in Metastatic Prostate Carcinoma Cells Correlates with Hyaluronan Surface Retention, a Prerequisite for Rapid Adhesion to Bone Marrow Endothelial Cells

Simpson, Melanie A.; Reiland, Jane; Burger, Scott R.; Furcht, Leo T.; Spicer, Andrew P.; Oegema, Theodore R.; McCarthy, James B.

doi:10.1074/jbc.m010064200

Cited by 100 publications

(106 citation statements)

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“…1 Highly metastatic PC3M-LN4 cells (1) were found to adhere rapidly to human bone marrow-derived sinusoidal endothelial cell lines, whereas poorly metastatic LNCaP cells were only weakly adherent (2). This adhesion, specific for BMECs relative to other endothelial cells, was subsequently found to depend upon the presence of a pericellular hyaluronan (HA) matrix assembled on the PC3M-LN4 cells.…”

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confidence: 96%

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Manipulation of Hyaluronan Synthase Expression in Prostate Adenocarcinoma Cells Alters Pericellular Matrix Retention and Adhesion to Bone Marrow Endothelial Cells

Simpson¹,

Wilson²,

Furcht³

et al. 2002

Journal of Biological Chemistry

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104

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Prostate cancer metastasis to bone marrow involves initial adhesion of tumor cells to the bone marrow endothelium, followed by transmigration and proliferation within the marrow. Rapid, specific adhesion of highly metastatic prostate adenocarcinoma cells Prostate cancer mortality is frequently the result of bone metastasis. The preferential homing of circulating prostate tumor cells to bone marrow is thought to involve an initial rapid adhesion to cells of the bone marrow endothelium, followed by transmigration of the endothelium, engagement of specific receptors, and subsequent proliferation within the bone marrow microenvironment. Molecular mechanisms underlying these processes are poorly understood, but there is evidence that tumor cells may exploit existing pathways utilized by circulating blood cell progenitors to gain access to bone marrow.To identify potential cell adhesion molecules involved in prostate tumor bone metastasis, research in our laboratory has focused on the interaction of prostate carcinoma cells with bone marrow endothelial cells (BMECs).1 Highly metastatic PC3M-LN4 cells (1) were found to adhere rapidly to human bone marrow-derived sinusoidal endothelial cell lines, whereas poorly metastatic LNCaP cells were only weakly adherent (2). This adhesion, specific for BMECs relative to other endothelial cells, was subsequently found to depend upon the presence of a pericellular hyaluronan (HA) matrix assembled on the PC3M-LN4 cells. The presence of pericellular HA further correlated with elevated HA synthesis and expression of HA biosynthetic enzymes in the metastatic cells. Collectively, our results may implicate tumor cell-associated HA and up-regulation of HA synthase (HAS) in prostate cancer progression, possibly by facilitating arrest in the bone microvasculature and/or preferential tissue colonization of individual tumor cells.

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“…In our previous report, we determined that HAS2 and HAS3, normally present at low levels in the prostate, are strongly up-regulated in metastatic prostate tumor cells (2). In this report, we have used the in vitro BMEC adhesion model to examine the role of these enzymes and their product in prostate cancer bone metastasis.…”

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confidence: 99%

Manipulation of Hyaluronan Synthase Expression in Prostate Adenocarcinoma Cells Alters Pericellular Matrix Retention and Adhesion to Bone Marrow Endothelial Cells

Simpson¹,

Wilson²,

Furcht³

et al. 2002

Journal of Biological Chemistry

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104

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“…For example, the rate of HA synthesis is enormously increased when oncogenic viruses transform fibroblasts (7,8), and elevated levels of HA are associated with the hyperproliferative and malignant phenotypes in melanomas and various carcinomas (9)(10)(11).…”

Section: H Yaluronan (Ha) Is a Linear Polysaccharide Composed Of A Rementioning

confidence: 99%

Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration

Itano

Atsumi

Sawai

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

276

197

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Elevated hyaluronan biosynthesis and matrix deposition correlates with cell proliferation and migration. We ectopically expressed three isoforms of hyaluronan synthase (HAS1, HAS2, or HAS3) in nontransformed rat 3Y1 cells and observed a de novo, massive formation of a hyaluronan matrix that resulted in a partial loss of contact-mediated inhibition of cell growth and migration. All three HAS transfectants showed an enhanced motility in scratch wound assays, and a significant increase in their confluent cell densities. In high-density cultures, the HAS transfectants had a fibroblastic cell shape and markedly formed overlapping cell layers. This phenotype was more pronounced in the HAS2 transfectants than HAS1 or HAS3 transfectants, and occurred with significant alterations in the microfilament organization and N-cadherin distribution at the cell-cell border. Inhibition of a phosphatidylinositol 3-kinase (PI3-kinase) pathway resulted in reacquisition of the normal phenotype of HAS2 transfectants, suggesting that the intracellular PI3-kinase signaling regulates diminution of contact inhibition induced by formation of the massive hyaluronan matrix. Our observations suggest that hyaluronan and its matrix can modulate contact inhibition of cell growth and migration, and provide evidence for functional differences between hyaluronan synthesized by the different HAS proteins.H yaluronan (HA) is a linear polysaccharide composed of a, and is widely present as a major component of extracellular matrix in most vertebrate tissues (1, 2). HA is synthesized by three HA synthase isoforms: HAS1, HAS2, and HAS3 (3, 4). The three HAS genes have distinct expression patterns during mouse development (5), and their products have significantly different enzymatic properties and roles in the formation of the HA matrix (6).HA synthesis and matrix formation may have a role in the development, progression and pathogenesis of cancer. For example, the rate of HA synthesis is enormously increased when oncogenic viruses transform fibroblasts (7,8), and elevated levels of HA are associated with the hyperproliferative and malignant phenotypes in melanomas and various carcinomas (9-11).Studies done with cultured cancer cells showed that overproduction of HA enhances their anchorage-independent growth, tumorigenicity, and metastatic potential (12, 13), suggesting an important role for HA in tumor growth and malignant progression. However, it was unclear whether the overproduction could induce a malignant transformation of nontransformed cells.We overexpressed the three HAS isoforms to test the ability of HA to transform nontransformed cells. We also investigated whether the three HAS isoforms are functionally distinct in nontransformed cells. Materials and MethodsCell Culture and Transfection. 3Y1 1-B6 cells were obtained from Riken Cell Bank (Tsukuba, Japan). The 3Y1 cells were cultured in DMEM containing 10% FCS and 2 mM L-glutamine (growth medium). Stable transfectants were established as previously described (6) and were routinely cultured in ...

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“…2,3 Such interactions of tumor pericellular hyaluronan may contribute to "seeding" or initial survival of tumor cells during early stages of metastasis to bone or other organs. A similar conclusion was reached in another study in which inhibition of mammary tumor cell interaction with hyaluronan led to their rapid apoptosis within hours of entry into the lung interstitium.…”

Section: Hyaluronan In Tumor Cell Growth and Survivalmentioning

confidence: 99%

“…In previous studies, these investigators showed that aggressive PC3M-LN4 human prostate carcinoma cells contain two of the three synthases that synthesize hyaluronan, namely HAS2 and HAS3, and that transfectants of PC3M-LN4 with antisense to HAS2 and HAS3 mRNA synthesized significantly less hyaluronan. 2,3 In the present study, stable transfectants with antisense-HAS2 and antisense-HAS3 were used alone or in combination to study tumor growth after subcutaneous injection in immunocompromised mice. The antisense-HAS transfectants produced tumors that were three to four times smaller than control tumors after 3 weeks.…”

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confidence: 99%

Hyaluronan and Tumor Growth

Toole

Hascall

2002

The American Journal of Pathology

113

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The study published in this issue of The American Journal of Pathology by Simpson et al 1 adds a new dimension to the role of hyaluronan in cancer by demonstrating that inhibition of endogenous hyaluronan synthesis dramatically reduces tumor growth in vivo. In previous studies, these investigators showed that aggressive PC3M-LN4 human prostate carcinoma cells contain two of the three synthases that synthesize hyaluronan, namely HAS2 and HAS3, and that transfectants of PC3M-LN4 with antisense to HAS2 and HAS3 mRNA synthesized significantly less hyaluronan. 2,3 In the present study, stable transfectants with antisense-HAS2 and antisense-HAS3 were used alone or in combination to study tumor growth after subcutaneous injection in immunocompromised mice. The antisense-HAS transfectants produced tumors that were three to four times smaller than control tumors after 3 weeks. Although inhibition of hyaluronan synthesis reduced rates of cell proliferation in culture, the antisense-HAS transfectant tumors contained similar proportions of dividing and apoptopic cells as did the control tumors at 3 weeks. This finding suggests that the reduced size of the antisense-HAS transfectant tumors is due to reduced rates of growth early in development of the tumor. The authors also found that blood vessel density was diminished by 70 to 80%, implying that hyaluronan levels may be an important determinant of vascularity, and that this rather than proliferation is the predominant factor in the effect of hyaluronan on tumor growth in this model. Interestingly, inclusion of exogenous hyaluronan with the initial injection of the transfected tumor cells restored levels of tumor growth and vascularity to those seen in control tumors, suggesting that early angiogenic events may be crucial.Numerous other studies have demonstrated a close correlation between tumor progression and hyaluronan production, either by tumor cells themselves or by stromal cells associated with tumors. This correlation has been observed in cell culture, in experimental animal models, and in human patients. In fact, recent work shows that hyaluronan content correlates with increased progression in several cancers, including breast, ovarian, prostate, and colorectal cancers. 4,5 In addition to the observation that hyaluronan is present in elevated amounts in numerous types of tumors, experimental manipulations of hyaluronan levels and interactions suggest a vital role for hyaluronan in promoting malignant cell behavior in vitro and in vivo. For example, experimental elevation of hyaluronan production in HT1080 human fibrosarcoma cells or TSU human prostate carcinoma cells enhances growth in vivo. 6,7 Also, low producers of hyaluronan selected from a population of mammary carcinoma cells are less metastatic than high producers, and metastatic capacity was restored to the low producers by elevating their hyaluronan production. 8 Hyaluronan-Receptor InteractionsHyaluronan interacts with several cell surface receptors, including CD44, RHAMM, LYVE-1, HARE, layilin, and Toll...

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Hyaluronan Synthase Elevation in Metastatic Prostate Carcinoma Cells Correlates with Hyaluronan Surface Retention, a Prerequisite for Rapid Adhesion to Bone Marrow Endothelial Cells

Cited by 100 publications

References 67 publications

Manipulation of Hyaluronan Synthase Expression in Prostate Adenocarcinoma Cells Alters Pericellular Matrix Retention and Adhesion to Bone Marrow Endothelial Cells

Manipulation of Hyaluronan Synthase Expression in Prostate Adenocarcinoma Cells Alters Pericellular Matrix Retention and Adhesion to Bone Marrow Endothelial Cells

Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration

Hyaluronan and Tumor Growth

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